Classification and aetiology
Fabry disease is one of at least 50 inherited lysosomal storage disorders (LSDs) that have a collective incidence of one per 7000 to 8000 live births.1 Each lysosomal storage disorder is caused by a genetic defect in a specific lysosomal enzyme, receptor target, activator protein, membrane protein, or transporter that causes lysosomal accumulation of specific substrates.
The genetic defect in Fabry disease is mutation of the GLA gene encoding α-galactosidase A, a lysosomal enzyme involved in the degradation of glycosphingolipids.2 Individuals with Fabry disease have absent or deficient α-galactosidase A activity.2 The clinical manifestations of the disease are thought to be consequences of lysosomal storage of accumulated α-galactosidase A substrates, particularly globotriaosylceramide (GL-3). Storage occurs in a variety of cell types.3
Impaired degradation of glycosphingolipids in Fabry disease
In common with most LSDs, Fabry disease is progressive. Accumulation of substrates over time causes cellular and tissue dysfunction eventually leading to organ failure.1 The classical presentation of the disease is multisystemic, involving the nervous system, kidneys, heart, gastrointestinal tract, skin, eyes and cerebral vasculature.2,4 However, there is increasing recognition of less common atypical presentations of Fabry disease that manifest predominantly in a single organ system.5,6 Multisystemic disease represents ‘classical’ Fabry disease, whereas individuals with predominantly monosystemic presentations are referred to as atypical variants.2
Progression of Fabry disease
Fabry disease is pan-ethnic. It has an estimated incidence of 1:4600 in New Born Screening studies with a 7:1 ratio of Atypical:Typical patients. Postnatal diagnosis shows a greater range of 1 in 40,000 to 1 in 117,000 males and an unknown incidence in females due to different populations and screening test sensitivity respectively.7-9 Although Fabry disease is an X-linked disorder, a wide spectrum of clinical phenotypes occurs in females due in part to skewed X chromosome inactivation.4
Other names for the disease
Fabry disease is also known as:
- Fabry’s disease
- Anderson-Fabry disease
- Alpha-galactosidase A deficiency
- Angiokeratoma corporis diffusum
- Ceramide trihexosidosis
- Ruiter-Pompen-Wyers syndrome
- Sweeley-Klionsky disease
Fabry disease was first described in 1898 by two independent dermatologists, William Anderson and Johannes Fabry. The underlying cause of the disease, α-galactosidase A deficiency and substrate accumulation, was discovered in 1967.
Fabry disease is an inherited disorder transmitted as an X-linked trait.